Ink formulations comprise mixtures of insoluble particles in a liquid vehicle and are widely used as a method of administering solid particles. Permanent and semi-permanent inks are suspensions of insoluble colorants. Additionally, many liquid oral medications are suspensions of insoluble active ingredients. A common concern in such a system is that insoluble particles tend to separate out of the mixture over time. Stability can affect the appropriate administration of a product.
In a mixture, insoluble solids inside a liquid matrix tend to aggregate and particle sedimentation can occur. Aggregation, the process by which smaller particles in a mixture combine together or flocculate, becomes more likely with increased particle size and concentration. Sedimentation, the process by which the particles gather at the bottom of the mixture due to density, becomes more likely as particles aggregate.
Suspensions and sol type dispersions are two common forms of mixtures of insoluble particles in a liquid vehicle. Mud, which is soil suspended in water, is a common suspension and blood is a common sol type dispersion.
Suspensions utilize suspending and rheology modifiers to suspend solids in a liquid matrix. The liquid matrix can be made thicker and suspending agents can be added as needed. This allows particles to be trapped in the web of the matrix for a time, lowering the rate of sedimentation. This is the method used when making a suspension such as many liquid oral medications.
Dispersions utilize particles that have been ground smaller and coated with a dispersing aid prior to addition to the liquid matrix. The coating is such that it has an affinity toward the liquid matrix which helps prevent the particles from aggregating. The insoluble particles can then be dispersed in the matrix and the coating on the particles allows for the particles to have a greater affinity for the matrix.
Dispersions are considered better for many pharmaceutical preparations because dispersions do not adhere to the normal laws of suspensions, such as Stoke's law. This allows for stability with fewer or no vehicle thickening agents. When flocculation is disregarded, sedimentation velocity can be seen in terms of Stoke's law:v=d2(ρs−ρl)g/18η
Where, v=Terminal settling velocity
d=Diameter of the settling particle
ρs =Density of the settling solid (dispersed phase)
ρl=Density of the liquid (dispersion medium)
g=Gravitational acceleration
η=Viscosity of the dispersion medium
By this law, the terminal settling velocity increases as the viscosity of the medium decreases. When the vehicle is water, thickeners are needed to create a more stable suspension. As more additives are introduced to the mixture, its viscosity increases resulting in greater stability. However, the higher viscosity lowers the ease of application and pourability of the mixture and re-dispersibility of the sediment. Since it is also known that any additive increases the chance of allergic reaction and can affect any active ingredient in the formulation, additives can limit the effectiveness and affect the dosage of certain formulations, particularly pharmaceutical preparations. Further side by side trials comparing dispersion stability to the stability of a like suspension is of great benefit to improving on pharmaceutical formulations.
Dispersions have a number of qualities that make them better candidates than suspensions for use in ink formulations. For example, there is very little to prevent aggregation and sedimentation in a suspension. Insoluble particles present in typical suspensions are large enough for sedimentation. Smaller insoluble particle size improves biocompatibility and reduces the speed of sedimentation. With dispersions, milling is used to create smaller particles than those used in suspensions. In addition, dispersions contain particles that have been encapsulated within a coating that has a higher affinity for the surrounding liquid than for other particles. The milling process in the dispersion allows for smaller particles while the encapsulation of particles helps slow the rate of aggregation and allows those particles to have a greater affinity for the liquid matrix. If properly made, a dispersion prevents aggregation and sedimentation, resulting in a more stable mixture with a more consistent density.
During certain medical procedures, there is a need to mark living human tissue with a substantially permanent ink. For example, during an endoscopy procedure, if lesions are found in a gastrointestinal (GI) tract of a patient, it is advantageous to mark the lesions to enable enhanced localization during surgery or subsequent endoscopies. Usually, a staining agent or ink is injected into a luminal mucosal surface for marking specific regions of the GI tract.
India ink has been commonly used as a staining agent for marking living tissue over several decades. It is composed of a colloidal suspension of carbon particles in a solution of organic and nonorganic substances used as stabilizing dilutants and surfactants. Other dyes for marking tissue include carbon particle suspension, methylene blue, indigo carmine, toluidine blue, lymphazurin, hematoxylin, eosin, and indocyanine green (ICG). It has been observed that India ink is a preferred staining agent in terms of safety, efficacy, and ease of use. Moreover, India ink is a more preferable staining agent due to its substantial permanence when compared to other approved dyes. However, the use of India ink as a living tissue staining agent is not without its drawbacks. For example, India ink stains containing higher concentrations of carbon have been known to cause inflammation and create abscesses in living tissue. Stains with lower concentrations of carbon often result in insufficient staining and therefore less than desirable tissue visualization.
Endoscopic dyeing agents other than India ink have been formulated to permanently stain living tissue without the associated side effects noted above. For example, U.S. Pat. No. 6,280,702, assigned to Chek-Med Systems, Inc., discloses an “endoscopic tissue staining composition comprising carbon pigment, suspending/viscosity-increasing agent in a pharmaceutically acceptable delivery vehicle, anti-foaming agent, and surfactant, said carbon pigment in an effective staining amount for internal mucosa and said suspending/viscosity-increasing agent in an effective amount for suspending carbon in solution and providing sufficient viscosity for endoscopic tissue staining ” In addition, U.S. Pat. No. 6,599,496, also assigned to Chek-Med Systems, Inc., discloses an “endoscopic tissue staining composition comprising a carbon pigment and a suspending/viscosity-increasing agent in a pharmaceutically acceptable delivery vehicle, wherein said carbon pigment has a level of total polycyclic aromatic hydrocarbons of not greater than 0.5 ppm.”
Conventional inks for marking living tissue, including India ink and formulations disclosed in the United States patents referenced above, are suspensions of carbon particles in a suspending agent. Typically, the process of forming suspensions involves increasing the viscosity of a suspending material, such as water, by using suspending/viscosity increasing agents and adding sufficient quantities of solubilizing agents to suspend carbon particles for a desired amount of time.
Suspensions are not an ideal choice for ink formulation for marking living tissue. This is because suspensions require a large number of additives in order to effectively suspend the carbon particles. The materials commonly used as additives in ink suspensions include large quantities of thickeners (5-25%), surfactants, and antifoaming agents. It is a common observation that in spite of using a variety of additives, the suspended carbon particles still have a tendency to precipitate within the suspension. Additionally, the use of large quantities of additives may cause the ink suspensions to become reactive to living tissue causing irritation and/or redness and swelling of the tissue. Typically, such reactions symptoms arise from allergic reactions which increase when the amount and variety of additives increase. Therefore, in patients with pre-existing problems, this can be extremely detrimental.
Hence, there is a need for an ink formulation for marking living tissue sites that is more stable than the available ink suspensions, while still providing a sufficient level of carbon to stain living tissue and not cause cell inflammation or cell death. There is also a need for an ink formulation that contains minimal or no additives such as thickeners, surfactants and antifoaming agents, thereby making the formulation non-reactive and safe for use with human tissue. Such an ink formulation can be put to a plurality of uses including, but not limited to, safe and effective marking of living tissue.